It is becoming a conventional therapy to treat solid tumors with chemotherapeutic drugs. Most of such drugs are associated with toxicities that affect the well being of patients subjected to such therapy. For example, despite the fact that paclitaxel, also known as Taxol, is one of the most potent and effective chemotherapeutic agents in the treatment of solid tumors, including stage 4 disease, a major drawback of the drug is its toxic effects on the bone marrow. In some cases it may also cause an anaphylactic shock, which may be fatal in spite of prophylactic hydrocortisone, and benadryl IV. Common side effects of paclitaxel include nausea and vomiting, loss of appetite, change in taste, thinned or brittle hair, joint pain in arms or legs, changes in color of nails, tingling in the hands or toes. More serious side effects include unusual bruising or bleeding, pain, redness and swelling at the injection site, changes in normal bowel habit, fever, chills cough, sore throat, difficulty swallowing, dizziness, shortness of breath, severe exhaustion, skin rash, facial flushing, female infertility by ovarian damage, and chest pain. Clinical toxicity of paclitaxel is associated with the solvent Cremophor EL in which it is dissolved for delivery.
Attempts at reducing toxicity of Taxanes, the class of medicines that includes compounds such as paclitaxel and docetaxel, have so far failed. Abraxane is an example; Abraxane (nab-paclitaxel) is paclitaxel bound to albumen nanoparticles. Abraxis BioScience developed Abraxane to reduce toxicity of paclitaxel by replacing the toxic solvent delivery method with Albumen. But clinical trials failed to show any advantage. The toxicity of paclitaxel is such that patients taking the drug are better off sleeping overnight in hospital. Mortality is high from bone marrow depression with low WBC with resulting septicemia and irreversible shock.
Honey has been used for more than 2000 years as traditional medicine in different cultures, particularly for its wound healing properties. The antimicrobial properties of honey have been well described in the literature. Intrinsic properties of honey like high osmolarity and acidity, as well as the presence of flavonoids and phenolic acids are responsible for its antibacterial and antioxidant activities (Watson et al. Food Chem 64: 295-301, 1999). In addition to its antimicrobial, antioxidant and tissue-protective activities, recent reports have highlighted multiple roles for honey in enhancing immune responses, including the induction of inflammatory cytokine production by macrophages (Tonks et al. Cytokine 21: 242-247, 2003), stimulation of neutrophil migration (Fukuda et al. Evid Based Complement Alternat Med, 2009) and enhanced antibody production (Al-Waili, J Med Food 7: 100-107, 2004). Whether the multitude of honey activities is mediated by the same or different active fractions remains to be fully elucidated.
Manuka honey, obtained from nectar collected by honey bees (Apis Mellifera) from the New Zealand manuka tree (Leptospermum scoparium), is a complex mixture of carbohydrates, fatty acids, proteins, vitamins and minerals containing various kinds of phytochemicals with high phenolic and flavonoid content (Yao et al. Food Chemistry 81: 159-168, 2003). While manuka honey shares constituents, e.g. glucose-oxidases, with other honeys it also contains other phytochemical factors that potentiate its antibacterial activity like methylglyoxal (Mavric et al., Mol Nutr Food Res 52: 483-489, 2008). This gave rise to a classification system adopted for active manuka honey, known as unique manuka factor (UMF), an indication of its antibacterial activity (Allen et al. J Pharm Pharmacol 43: 817-822, 1991).
Previous studies addressing the mechanisms of the anti-bacterial activity of manuka honey identified a number of potential active constituents, including several phenolic compounds that act as scavengers of superoxide anion radicals (Inoue et al., J Sci Food Agri 85: 872-878, 2005, Jenkins et al, Jenkins et al. Int J Antimicrob Agents 37: 373-376, 2011, Kawakman et al, PLoS One 6: e17709, 2011). There is evidence that the antibacterial activity of manuka honey is independent of its role in inducing inflammatory cytokines during innate immune responses.
A 5.8 kD, heat-sensitive, protease-resistant, component, that was devoid of any antibacterial activity was identified to be responsible for the induction of cytokine production via interaction with TLR4 on macrophages (Tonks et al. J Leukoc Biol 82: 1147-1155. 2007). These studies suggest the presence of unique, yet-to-be-characterized, constituents with desired activities in manuka honey. However, an investigation of the anti-proliferative properties of manuka honey has not been undertaken.
Perhaps, one of the oldest known uses for honey is in wound healing. There is extensive scientific and clinical evidence to support the utilization of honey for wounds, skin reactions and damage to epithelial barriers following radiotherapy and chemotherapy (Bardy et al, J Clin Nurs 17: 2604-2623 2008). In patients with chronic wounds or burns, honey has been shown to stimulate angiogenesis and epithelialization, promoting more efficient healing (Molan Am J Clin Dermatol 2: 13-19 2001, Wijesinghe N Z Med J 122: 47-60, 2009). More recently, several reports demonstrated that honey, being rich in polyphenols and flavonoids, has anti-proliferative effects against cancer cells (Jaganathan et al. J Biomed Biotechnol 2009: 830616, 2009, Ghashm et al. BMC Complement Altern Med 10: 49, 2010, Swellam et al. Int J Urol 10: 213-219, 2003). However, the mechanisms for the anti-cancer effect are still to be fully elucidated. In an early study, honey was shown to exhibit modest anti-tumor, but good anti-metastatic, activities against a number of tumor cell lines (Gribel & Pashinskii Vopr Onkol 36: 704-709, 1990). Another study extended this observation and showed that dietary intake of caffeic acid esters, a major constituent of Propolis honey beehives, inhibited the incidence and multiplicity of invasive and non-invasive carcinogen-induced colon adenocarcinomas (Rao et al Cancer Res 53:4182-4188, 1993). More recently, diluted unfractionated honey was shown to inhibit the proliferation of bladder cancer cell lines in vitro. Moreover, intralesional injection of honey was found to inhibit tumor growth in a bladder cancer implantation mouse model, but the effect of the treatment on animal survival was not reported (Swellam et al. Int J Urol 10: 213-219, 2003).
The effect of manuka honey on the growth of cancer cells, using both in vitro as well as in vivo approaches, was investigated. The findings provide mechanistic evidence for the induction of apoptosis in cancer cells by manuka treatment and further highlight a novel role for systemically-administered manuka honey as both an anti-cancer agent and an adjuvant in combination with standard chemotherapeutic agents. Moreover, the data provides direct evidence that manuka honey administration reverses the systemic toxicity associated with the use of a chemotherapeutic agent, such as paclitaxel.